A Prospective Clinical Trial to Evaluate Mesothelin as a Biomarker for the Clinical Management of Esophageal Adenocarcinoma (EAC) Patients The incidence of esophageal adenocarcinoma (EAC) is rising at an annual rate of 8%. Most EAC patients present at an advanced stage disease with an overall 5-year survival rate of 10%. Of the patients who present with potentially curable disease, majority will already have local-regional advanced disease. Although combined modality treatment, the current standard of care for locally advanced disease, improves survival, lack of accurate clinical evaluation of tumor burden and treatment response is a significant limitation in selecting appropriate treatment in a timely fashion. In spite of the radiographic and endoscopic imaging, one in four patients with a presumed early-stage disease are found to have more extensive disease (T3 or N1) at the time of surgery. These patients would have benefited from multimodality therapy. In patients treated with neo- adjuvant therapy for local-regional advanced disease, assessment of therapy response remains inaccurate. Identification and validation of a biomarker that reflects tumor burden, therapy response, and recurrence will be highly valuable for the clinical management and clinical trials of EAC patients. In this research proposal, based on our promising retrospective data, we aim to investigate serum and tissue mesothelin as a biomarker to improve the clinical management of EAC patients. Mesothelin is a cell surface tumor-differentiation antigen, the N-terminal of which is cleaved and secreted into blood, measured as serum soluble mesothelin-related peptide (SMRP). Increased SMRP levels are demonstrated in mesothelioma, pancreatic and ovarian cancer patients. Recent publications have demonstrated that the level of SMRP correlates with tumor load, therapy response, and prognosis in mesothelioma patients. We propose: Specific Aim 1: To prospectively evaluate whether serum SMRP levels correlate with (a) clinical staging, (b) response to neo-adjuvant therapy, and (c) disease recurrence in surgically resected EAC patients. Specific Aim 2: To prospectively investigate whether tissue mesothelin expression (a) pre chemo-radiation therapy is a predictor of poor therapy response, and (b) post-resection is a predictor of poor survival. The novelty and impact of this carefully designed prospective proposal extends beyond biomarker study in testing the utility of mesothelin as a marker of Barrett's transformation to EAC; it is immediately translational to benefit 15,000 patients with EAC. PUBLIC HEALTH RELEVANCE: A simple predictive instrument to identify early-stage esophageal adenocarcinoma patients at higher risk for poor therapy response and recurrence; therefore the most likely candidates for selection of therapeutic modality or aggressive surveillance will benefit. In this research proposal, based on our promising retrospective data, we aim to investigate serum and tissue mesothelin as a biomarker to improve the clinical management of esophageal adenocarcinoma patients.